Occurrence of early onset, multi-focal and bilateral kidney cancers in first degree relatives led Fred Li and colleagues to show that clear cell renal cancer in that family segregated with a balanced chromosome translocation, t(3;8) involving the short arm of chromosome 3. We used the chromosome breakpoints of the translocation, in conjunction with loss of heterozygosity studies, to positionally clone the FHIT gene and characterize its structure and expression in a large variety of cancer types, including RCC. The FHIT gene, at the FRA3B fragile region is a target of tobacco carcinogens and FHIT protein expression is lost at the early squamous metaplasia stage of bronchial pre-neoplasia. Our collaboration with members of the Genetics and Pathology Department of the Medical Academy at Szczecin, which began before 1990, was important in development of the FHIT study and is critical in our planned collaboration. Jacek Podolski and colleagues in Szczecin discovered a second familial clear cell RCC-associated chromosome translocation and has completed preliminary positional cloning of the involved chromosome regions during his Fogarty fellowship in the PI's laboratory. During the extension of this collaborative study we propose to: isolate and characterize the genes altered by the translocation breaks; determine tissue specific of expression and characterize the structure and expression of the full length gene(s) in normal cells and cells carrying the translocation; determine if the gene structure and expression is altered in sporadic RCCs and other cancers; express recombinant protein in pro-karyotic (for anti-serum production) and eukaryotic cells for study of biological effects; study expression of the candidate gene product in cancer tissue sections by immunohistochemistry. The long term goal is to understand the role of the candidate gene(s) in initiation and progression of clear cell renal carcinoma and determine diagnostic or prognostic usefulness.